Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. U.S. Pat. No. 5,478,820 to Betts et al, issued Dec. 26, 1995, now assigned to Zeneca Ltd. (incorporated herein by reference thereto), teaches carbapenem compounds, salts and hydrolysable esters thereof, of the general formula I:
wherein R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl, R2 and R3 are hydrogen or C1-4 alkyl, and R4 and R5 are hydrogen, halo, cyano, nitro, hydroxy, alkylamino, aminosulphonyl, or carbamoyl.
Crystalline forms of carbapenem antibiotics are desirable for improved purity and stability compared with amorphous forms. Crystallization allows isolation of a compound with rejection of impurities, and crystalline forms tend to be more stable than amorphous forms of the same compound. In the present invention, crystalline forms of the carbapenem (4R,5S,6S,8R,2′S,4′S)-3-[[2-[[(3-carboxyphenyl) amino]carbonyl]pyrrolidin-4-yl]thio]-4-methyl-6-(1-hydroxyethyl)-7-oxo1-azabicyclo [3.2.0]hept-2-en-2-carboxylic acid have been discovered and characterized and the processes for making said forms are disclosed.
The compounds of formula I can generally be synthesized taking into account the disclosure of U.S. Pat. No., 6,063,931 granted May 16, 2000, U.S. Pat. No. 5,648,501 granted Jul. 15, 1997, U.S. Pat. No. 5,478,820 granted Dec. 26, 1995, U.S. Pat. No. 6,180,783 granted Jan. 30, 2001, U.S. Pat. No. 5,872,250 granted Feb. 16, 1999 and U.S. Pat. No. 5,965,747, granted Oct. 12, 1999 (all incorporated herein by reference). See also Bugay, D. E., Pharm. Res., 1993, 10, 317; Harris, R. K., et al., Spectrochimica Acta, 1989, 45A, 465; Byrn, S. R., et al., J. Pharmaceutical Sciences, 1985, 74, 565.